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Expert Details Ongoing JAK Inhibitor Development in MPN Treatment Paradigm

Caroline Seymour
Published Online:9:09 PM, Fri December 21, 2018

Stephen Oh, MD, PhD

The JAK1/2 inhibitor ruxolitinib (Jakafi) has played an integral role in the treatment of patients with myelofibrosis and polycythemia vera (PV); however, additional selective JAK inhibitors, such as momelotinib, pacritinib, and fedratinib are showing encouraging progress in the treatment paradigm, explained Stephen Oh, MD, PhD.

“At this point, it's impossible to say that momelotinib, pacritinib, or fedratinib is really a frontrunner. Rather, I'd say that they potentially offer slight distinctions between each other and ruxolitinib,” said Oh. “I could envision a scenario where if all of these agents were available, there could be specific niches for each of these particular drugs for specific types of patients.”

In 2011, the JAK1/2 inhibitor ruxolitinib (Jakafi) was approved by the FDA for patients with intermediate- and high-risk myelofibrosis. Three years later, it was approved for patients with PV who are intolerant or resistant to hydroxyurea. Although it shows significant symptom reduction in patients with PV, other agents need to be added to the armamentarium.

In an interview with Targeted Oncology, Oh, assistant professor of medicine, Division of Hematology, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discussed the use of ruxolitinib in patients with myelofibrosis and PV, and emerging agents and next steps in the field of MPNs.

TARGETED ONCOLOGY:  What are the new prognostic factors for myelofibrosis?

Oh: Historically we've used the International Prognostic Scoring System (IPSS), the dynamic IPSS (DIPSS), or the DIPSS-plus for risk stratification. This system does not take into account any of the particular molecular markers in this disease. More recently, we’ve learned about specific driver mutations such as JAK, CALR, and MPL, but also, that many patients harbor concomitant mutations and other driver mutations such as ASXL1, and in some cases, IDH1/2. Some of the more recently published prognostic scoring systems are taking these into account, one of which is the Mutation-Enhanced IPSS 70. This system incorporates some of these high-risk mutations such as ASXL1, so that we can better understand the impact of these types of mutations on long-term prognosis. This is becoming particularly more relevant as many practitioners are beginning to test for these types of mutations in routine clinical practice.

TARGETED ONCOLOGY:  Where do the JAK inhibitors stand in development?

Oh: Each of the other JAK inhibitors besides ruxolitinib has had various issues, ranging from safety concerns to FDA holds, in some cases. The unique aspect of momelotinib is that it seems to improve anemia in a subset of patients. The drug was being developed by Gilead Sciences, but was later discontinued. Very recently, the rights to that drug were acquired by Sierra Oncology. At this point, it sounds like there are plans for further development of the drug, but we'll have to see.

The unique aspect of pacritinib, at least in part, is that it seems to be safe for patients even with a very low platelet count. There was an FDA hold for that drug due to safety concerns. That hold was lifted, and a new study is ongoing to determine the lowest dose that can be safely and effectively administered. It'll still be some time before that drug will potentially be approved, but it's still a viable candidate.

Fedratinib had been put on an FDA hold due to reports of Wernicke-like encephalopathy syndrome in several patients. The FDA hold has been lifted, and that drug is now being redeveloped by Celgene. We'll see with a new study going forward if that pans out.

TARGETED ONCOLOGY:  How do those inhibitors differ from ruxolitinib?

Oh: Each of these inhibitors has a slight distinction from ruxolitinib. As a class, these drugs seem to provide at least some degree of symptom benefit and spleen improvement. Some patients on momelotinib have anemia improvement, which is very different from ruxolitinib. Anemia improvement is essentially never seen with ruxolitinib; in fact, some patients will experience worse anemia on ruxolitinib.

With pacritinib, there's very little effect on the platelet count. It seems that this drug appears to be safely administered in patients with a platelet count below 50. That is definitely not the case with ruxolitinib. Current recommendations are to avoid using it with a platelet count below 50.

Fedratinib is distinct, to some extent, from ruxolitinib in that it is more selective for JAK as opposed to both JAK1/2. It also hits FLT3, which isn’t affected by ruxolitinib; whether or not that has any particular relevance in the case of myelofibrosis is not clear.

TARGETED ONCOLOGY:  What does the future hold for myelofibrosis treatment?

Oh: We have a class of drugs that can provide some degree of symptom benefit, spleen response, and some differential effects in terms of anemia response or safety. In the next 5 years, we’re hoping to have new options that are capable of ameliorating the underlying bone marrow fibrosis and improving cytopenias. Of course, we hope that there are going to be agents capable of putting patients into remission and modifying long-term outcomes.

TARGETED ONCOLOGY:  Does ruxolitinib show the same impact in PV as it does in myelofibrosis?

Oh: It's interesting when thinking about the use of ruxolitinib in PV in the context of its preexisting approval for myelofibrosis. On one hand, many patients with PV will do very well with conventional treatments, such as phlebotomy or hydroxyurea. I've found that ruxolitinib can be very effective for symptoms. In that way, it's analogous to [its use in] myelofibrosis.

Significant problems with itching are unique to patients with PV. This classic aquagenic pruritus occurs or can be exacerbated by taking a hot shower; that can range from a mild nuisance to being debilitating in some patients. Ruxolitinib is highly effective for that particular symptom as well as other symptoms associated with PV. I find that patients who are having these troublesome symptoms who may have had problems with hydroxyurea tend to do quite well with ruxolitinib. It tends to be a very durable and elicit effective responses.

TARGETED ONCOLOGY:  What are the unanswered questions in PV?

Oh: There is continued interest with various forms of interferon for PV and other MPNs. There are a couple of ongoing studies for which should updated data will be presented at the 2018 ASH Annual Meeting.

There is still this question of where interferon fits in the armamentarium. Should it be considered a preferred agent over hydroxyurea? Where does it fit when you also have ruxolitinib?

Also, similar to myelofibrosis, we need to look for therapies that have the possibility of modifying the long-term outcome of this disease; that could be in combination with existing therapies or completely novel mechanisms.

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